EP1052973A1 - Transmucosal formulations of levosimendan - Google Patents
Transmucosal formulations of levosimendanInfo
- Publication number
- EP1052973A1 EP1052973A1 EP98959930A EP98959930A EP1052973A1 EP 1052973 A1 EP1052973 A1 EP 1052973A1 EP 98959930 A EP98959930 A EP 98959930A EP 98959930 A EP98959930 A EP 98959930A EP 1052973 A1 EP1052973 A1 EP 1052973A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- levosimendan
- pharmaceutically acceptable
- acceptable salt
- mucous membrane
- oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WHXMKTBCFHIYNQ-SECBINFHSA-N levosimendan Chemical compound C[C@@H]1CC(=O)NN=C1C1=CC=C(NN=C(C#N)C#N)C=C1 WHXMKTBCFHIYNQ-SECBINFHSA-N 0.000 title claims abstract description 57
- 229960000692 levosimendan Drugs 0.000 title claims abstract description 56
- 239000000203 mixture Substances 0.000 title description 10
- 238000009472 formulation Methods 0.000 title description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 13
- 210000002200 mouth mucosa Anatomy 0.000 claims abstract description 11
- 210000002850 nasal mucosa Anatomy 0.000 claims abstract description 11
- 206010019280 Heart failures Diseases 0.000 claims abstract description 5
- 230000003232 mucoadhesive effect Effects 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- 239000011159 matrix material Substances 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 11
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- 239000006189 buccal tablet Substances 0.000 description 7
- -1 MethocelTM K100 Chemical compound 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229940046011 buccal tablet Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 210000005178 buccal mucosa Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019886 MethocelTM Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002125 SokalanĀ® Polymers 0.000 description 1
- 229920002807 Thiomer Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940068939 glyceryl monolaurate Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Definitions
- the present invention relates to transmucosal delivery of levosimendan or a pharmaceutically acceptable salt thereof, particularly delivery via oral and nasal mucosa.
- the invention also relates to transmucosal, particularly intraoral and intranasal, e.g. buccal, sublingual or sinuidal, preparations comprising levosimendan or a pharmaceutically acceptable salt thereof as the active ingredient.
- Levosimendan which is the (-)-enantiomer of [[4-(1 ,4,5,6-tetrahydro- 4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I), and the method for its preparation is described e.g. in EP 565546 B1.
- Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin.
- the use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921.
- Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(SupplJ ), S57-S62, 1995.
- levosimendan transmucosally preferably to oral or nasal mucosa.
- the occurence of undesired side effects such as headache and palpitation connected to the oral administration of levosimendan can be reduced or totally avoided.
- active metabolites formed in the gastrointestinal tract by intestinal bacteria contribute to the observed undesired effects. The formation of metabolites in the gastrointestinal tract can be reduced or totally avoided by transmucosal administration.
- the object of the invention is to provide a method for administering transmucosally, i.e. to and across a mucosal surface, levosimendan or a pharmaceutically acceptable salt thereof.
- the mucosal surface is preferably oral or nasal mucosa such as the buccal mucosa, the sublingual mucosa, the sinuidal mucosa, the gum, or the inner lip.
- the present invention also provides transmucosal, particularly intraoral and intranasal, e.g. buccal, sublingual or sinuidal, preparations comprising levosimendan or a pharmaceutically acceptable salt thereof as a therapeutically active ingredient.
- the present invention also provides the use of levosimendan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for transmucosal administration, particularly to oral and nasal mucosa, of levosimendan or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for treating heart failure comprising administering transmucosally, particularly to oral and nasal mucosa, a therapeutically effective amount of levosimendan or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
- the present invention provides a method of administering transmucosally, particularly to oral and nasal mucosa, levosimendan or a pharmaceutically acceptable salt thereof to a patient, wherein the method comprises contacting an intact mucous membrane with a source of levosimendan or a pharmaceutically acceptable salt thereof, and maintaining said source in contact with said mucous membrane for a sufficient time period to deliver said levosimendan or a pharmaceutically acceptable salt thereof to the patient.
- Fig. 1 illustrates the in vitro release of levosimendan from different mucoadhesive buccal preparations. Detailed description of the invention
- the transmucosal administration of levosimendan or a pharmaceutically acceptable salt thereof can be accomplished generally by contacting an intact mucous membrane with a source of levosimendan or a pharmaceutically acceptable salt thereof, and maintaining said source in contact with said mucous membrane for a sufficient time period to induce the desired therapeutic effect.
- the drug is administered to oral or nasal mucosa such as the buccal mucosa, the sublingual mucosa, the sinuidal mucosa, the gum, or the inner lip.
- the precise amount of the drug administered according to the invention is dependent on numerous factors, such as age and body weight of the patient, the condition of the patient and the desired duration of use.
- the daily dose of levosimendan to human patients is within the range of about 0J to 500 mg, preferably 0.5 to 10 mg.
- the blood concentration of levosimendan in human patients can be about 1-300 ng/ml, preferably 10- 150 ng/ml, especially 20-60 ng/ml.
- the time period for administering levosimendan from a sustained release preparation such as an transmucosal patch is from about 4 to 24 hours, typically about 12 hours.
- the source of the drug can be any transmucosal preparation suitable for administering levosimendan or a pharmaceutically acceptable salt thereof.
- the source of the drug is any preparation usable in oral, nasal, sinuidal or vaginal cavities that can be formulated using conventional techniques well known in the art.
- Preferred preparations are those usable in oral or nasal cavities.
- the preparation can be a buccal tablet, a sublingual tablet, a spray, and the like preparation that dissolve or disintegrate, delivering drug into the mouth of the patient.
- a spray or drops can be used to deliver the drug to nasal or sinuidal cavities.
- Said preparation may or may not deliver the drug in a sustained fashion.
- the manufacture examples for such preparations are disclosed for example in U.S. patent 4,764,378.
- the source of the drug is a mucoadhesive preparation.
- a mucoahdesive preparation is a preparation which upon contact with intact mucous membrane adheres to said mucous membrane for a sufficient time period to induce the desired therapeutic effect.
- the preparation can be a semisolid composition as described e.g. in WO 96/09829. It can be a tablet, a powder, a gel or film comprising a mucoadhesive matrix as described e.g. in WO 96/30013.
- the preparation can also be a syrup that adheres to the mucous membrane.
- Suitable mucoadhesives include those well known in the art such as polyacrylic acids, preferably having the molecular weight between from about 450,000 to about 4,000,000, e.g. CarbopolTM 934P; sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), e.g. MethocelTM K100, and hydroxypropylcellulose.
- CarbopolTM 934P sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), e.g. MethocelTM K100, and hydroxypropylcellulose.
- the preparation can also be in the form of a bandage, patch, device and the like preparation that contains the drug and adheres to a mucosal surface.
- Suitable transmucosal patches are described for example in WO 93/23011.
- a suitable patch may comprise a backing.
- the backing can be any flexible film that prevents bulk fluid flow and provides a barrier for to loss of the drug from the patch.
- the backing can be any of the conventional materials such as polyethylene, ethyl-vinyl acetate copolymer, polyurethane and the like.
- the drug-containing matrix can be coupled with a mucoadhesive component (such as a mucoadhesive described above) in order that the patch may be retained on the mucosal surface.
- a mucoadhesive component such as a mucoadhesive described above
- Suitable configurations include a patch or device wherein the matrix has a smaller periphery than the backing layer such that a portion of the backing layer extends outward from the periphery of the matrix.
- a mucoadhesive layer covers the outward extending portion of the backing layer such that the underside of the backing layer carries a layer of mucoadhesive around its periphery.
- the backing and the peripheral ring of mucoadhesive taken together form a reservoir which contains a drug- containing matrix (e.g. a tablet, gel, or powder).
- a drug- containing matrix e.g. a tablet, gel, or powder.
- the barrier element is preferably substantially impermeable to water and to the mucosal fluids that will be present at intended site of adhesion.
- a patch or device having such barrier element can be hydrated only through a surface that is in contact with the mucosa, and it is not hydrated via the reservoir.
- patches can be prepared by general methods well known to those skilled in the art.
- Preparations usable according to the invention can contain pharmaceutical ingredients, such as fillers, lubricants, disintegrants, solubilizing vehicles, flavours, dyes and the like. It may be desirable in some instances to incorporate a mucous membrane penetration enhancer into the preparation. Suitable penetration enhancers include anionic surfactants (e.g. sodium lauryl sulphate, sodium dodecyl sulphate), cationic surfactants (e.g. palmitoyl DL camitine chloride, cetylpyridinium chloride), nonionic surfactants (e.g.
- anionic surfactants e.g. sodium lauryl sulphate, sodium dodecyl sulphate
- cationic surfactants e.g. palmitoyl DL camitine chloride, cetylpyridinium chloride
- nonionic surfactants e.g.
- polysorbate 80 polyoxyethylene 9-lauryl ether, glyceryl monolaurate, polyoxyalkylenes, polyoxyethylene 20 cetyl ether), lipids (e.g. oleic acid), bile salts (e.g. sodium glycocholate, sodium taurocholate), and related compounds.
- lipids e.g. oleic acid
- bile salts e.g. sodium glycocholate, sodium taurocholate
- Example 1 Bioavailability of levosimendan following buccal and intravenous administration in dogs.
- Bioavailability of levosimendan was studied in dogs following buccal and intravenous administration of 0.02 mg/kg of the compound. As experimental animals, three beagle dogs were used. At the time of dosing all animals weighed approximately 10 kg. The dogs were given levosimendan as an intravenous injection or buccal spray at one week intervals. Appropriate concentration (2 mg/ml in 96 % ethanol) of the compound was prepared in 10 ml amber glass containers sealed with spray nozzles (50 ā l dose, Pfeiffer). The 0.02 mg/kg buccal dose was thus obtained by spraying 2 consecutive 50 ā l doses to the buccal cavity of the animals (the dosing volume being thus 0J ml/10 kg). The iv dose (0J ml/10kg) was taken from the same bottles.
- Levosimendan in dog plasma was determined by a non- enantioselective method, in which an automated sample preparation technique combined with high performance liquid chromatography was used.
- the plasma clean-up was performed by on-line dialysis and the dialysate was retained on a trace enrichment column.
- the analyte was then separated on an analytical column and detected with a UV-detector.
- the limit of quantitation was 5 ng/ml and the quantitation range 5-500 ng/ml.
- the apparatus comprised a Gilson ASTED (Automated Sequential Trace Enrichment System) system (Gilson Medical Electronics, V Amsterdam-le- Bel, France).
- the dialysis cell was fitted with a Cuprophan cellulose membrane with a molecular cut-off of 15 kDa and the trace enrichment column was a Hypersil ODS (5.8 x 4.6 mm i.d., 10 ā m).
- the chromato- graphic system consisted of an LKB Model 2150 pump (Bromma, Sweden) and a Lichrosorb RP-18 (250 x 4 mm i.d., 10 ā m) column (Merck, Darmstadt, Germany).
- the detector was a Spectra 100 UV-VIS (Spectra-Physics, San Jose, CA, USA). The wavelength was 380 nm.
- the mobile phase consisted of a 32 ITIM monosodium dihydrogen phosphate buffer, methanol, and tetrahydrofuran (45:65:1 , v/v/v, pH 3.5).
- the mobile phase flow rate was 1.0 ml/min.
- Table 1 shows that levosimendan is rapidly absorbed into blood from the buccal spray and steady serum levels of levosimendan are obtained.
- Example 2 Preparation of mucoadhesive buccal tablets and in vitro release experiment
- Buccal tablets described above were prepared by mixing powders needed for a batch of desired size in Turbula mixer and pressing in a tablet press using 7 mm punchs and 5 - 8 kN compression force.
- the thickness of the tablets was about 1.8 mm.
- the release of levosimendan from the preparations was studied using the paddle method according to USP XXII.
- the dissolution medium was phosphate buffer pH 5.8.
- the rotation speed of the paddles 50 rpm.
- Figure 1 shows the release (%) of levosimendan vs. time (h) from the buccal tablets of Table 2. All preparations acted as long-acting prepara- tions. Preparations I, II, III and V released levosimendan according to zero order kinetics up to 10 hours. The addition of NaCMC increased the release of levosimendan from buccal tablets. The figure shows that the position of the release curve may be systematically adjusted with the aid of amount and type of the mucoadhesive polymer.
- the legends in Figure 1 mean ā formulation I ā formulation II D formulation III V formulation IV ā formulation V
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SI9830182T SI1052973T1 (en) | 1997-12-19 | 1998-12-11 | Transmucosal formulations of levosimendan |
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FI974578 | 1997-12-19 | ||
FI974578A FI974578A (en) | 1997-12-19 | 1997-12-19 | Method of administering levosimendan |
PCT/FI1998/000977 WO1999032081A1 (en) | 1997-12-19 | 1998-12-11 | Transmucosal formulations of levosimendan |
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US (1) | US6399610B1 (en) |
EP (1) | EP1052973B1 (en) |
JP (1) | JP2001526205A (en) |
KR (1) | KR100753689B1 (en) |
AT (1) | ATE215358T1 (en) |
AU (1) | AU738082B2 (en) |
BR (1) | BR9813641A (en) |
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DE (1) | DE69804678T2 (en) |
DK (1) | DK1052973T3 (en) |
EA (1) | EA002197B1 (en) |
EE (1) | EE04330B1 (en) |
ES (1) | ES2175827T3 (en) |
FI (1) | FI974578A (en) |
HR (1) | HRP20000400B1 (en) |
HU (1) | HU226736B1 (en) |
IL (1) | IL136415A (en) |
NO (1) | NO320050B1 (en) |
NZ (1) | NZ504806A (en) |
PL (1) | PL191868B1 (en) |
PT (1) | PT1052973E (en) |
RS (1) | RS49889B (en) |
SK (1) | SK284838B6 (en) |
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ZA (1) | ZA9811405B (en) |
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FI980901A (en) * | 1998-04-23 | 1999-10-24 | Orion Yhtymae Oyj | Oral compositions that controlled release the levosimendan |
FI20002755A0 (en) | 2000-12-15 | 2000-12-15 | Orion Yhtymae Oyj | Method of therapy for erectile dysfunction |
CN100428937C (en) * | 2003-10-30 | 2008-10-29 | åäŗ¬ęµ·å天ē§ęå¼åęéå ¬åø | Levosimendan freeze-drying composition |
FI20040674A0 (en) * | 2004-05-12 | 2004-05-12 | Orion Corp | A method of inhibiting thromboembolic diseases |
EP1848270B1 (en) * | 2005-02-17 | 2014-05-21 | Abbott Laboratories | Transmucosal administration of drug compositions for treating and preventing disorders in animals |
CA2596768A1 (en) * | 2005-02-18 | 2006-08-24 | Orion Corporation | A method for treating heart failure |
WO2007096906A2 (en) * | 2006-02-27 | 2007-08-30 | Panacea Biotec Ltd. | Novel buccoadhesive compositions and process of preparation thereof |
CN101516426A (en) * | 2006-09-27 | 2009-08-26 | å°¼å čÆŗå§č”ä»½å ¬åø | Directional use |
EP3941450A4 (en) * | 2019-03-22 | 2022-12-21 | Dbbh, Llc | Intranasally administered antihistamines and uses thereof |
WO2021001601A1 (en) * | 2019-07-01 | 2021-01-07 | Orion Corporation | Methods for administering (r)-n-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide |
CA3161960A1 (en) | 2019-12-16 | 2021-06-24 | Tenax Therapeutics, Inc. | Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (ph-hfpef) |
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GB2251615B (en) * | 1991-01-03 | 1995-02-08 | Orion Yhtymae Oy | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]pro panedinitrile |
GB2266841A (en) | 1992-05-06 | 1993-11-17 | Orion Yhtymae Oy | Compounds for use as anti-ischemic medicaments |
US5688520A (en) * | 1995-03-29 | 1997-11-18 | Minnesota Mining And Manufacturing Company | Transmucosal delivery of melatonin for prevention of migraine |
GB9614098D0 (en) | 1996-07-05 | 1996-09-04 | Orion Yhtymae Oy | Transdermal delivery of levosimendan |
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